1. Field
The invention relates to the use of dimethyl carbonate ("DMC") for the N-methylation of indole compounds.
2. Description
The compound 3-(1-methylindol-3-yl)4-(1-methyl-6-nitroindol-3-yl)-1 H-pyrrole-2,5-dione is a selective inhibitor of protein kinase C ("PKC") and is useful as an antimitotic agent for oral treatment of solid tumors as well as treating autoimmune diseases such as rheumatoid arthritis. This compound is described in U.S. Pat. No. 5,057,614, the contents of which are herein incorporated by reference. A synthetic route for preparing this compound uses methyl iodide as a methylating agent (see for example, U.S. application Ser. No. 09/268,887, the contents of which are herein incorporated by reference, which shows the use of methyl iodide for the N-methylation of an indole to synthesize similar compounds). Unfortunately, methyl iodide is highly toxic and has a low boiling point. The release of methyl iodide into the air is highly restricted. Accordingly, there exists a need for environmentally friendly methods for methylating indole compounds.
The following scheme shows a method for preparing 3-(1-methyl-3-indolyl)4-(1-methyl-6-nitro-3-indolyi)-1 H-pyrrole-2,5-dione. ##STR3##
Common methylating agents, such as methyl halides (MeX; X.dbd.CI, Br, I) and dimethylsulfate ("DMS", can be used to methylate O--, C-- and N-- under mild reaction conditions. However, as described above for methyl iodide, these agents pose severe concerns from environmental and process safety standpoints. On the other hand, dimethyl carbonate is a comparatively safe, non toxic and environmentally friendly methylating agent. The by-products of its use, methanol and carbon dioxide, are not associated with disposal problems. Moreover, for the manufacture of antimitotic agents of the above class, which require two indole ring methylations, the need is double. Although it has been reported (Tondo, P., Selva, M., and Bomben, A., Org, Synth. 1998, 76, 169) that DMC can be used to methylate the alpha position of an arylacetonitrile, nowhere has it been suggested to use DMC for methylating indole ring containing compounds, much less the N-methylation of indole rings.
Unfortunately, the use of DMC in prior art processes typically requires high reaction temperatures (&gt;180.degree. C.), a stainless steel autoclave, high pressure, and a large excess of dimethyl carbonate (as solvent and methylating agent). With the help of catalysts, lower reaction temperatures (100.degree. C.) can be used. However, such catalysts (e.g. crown ether) are generally very toxic and pressurized reaction chambers are required.
The inventive use of dimethyl carbonate for N-methylation of an indole ring forms a part of the subject invention and was disclosed in U.S. Provisional Patent Application No. 60/171,557, filed Dec. 22, 1999, which is not publicly available. Although disclosed in this provisional application, the subject invention was not invented by the inventors named in the mentioned provisional patent application and forms no part of the invention claimed in that application.
Therefore, the subject invention fulfills a need in the art for a green process for methylating the nitrogen atom in an indole compound under conditions that do not require high pressure or temperature.